Iontophoretic delivery device

ABSTRACT

An electrically powered iontophoretic delivery device is provided. The device utilizes electrodes composed of a preferably hydrophobic polymeric matrix. The matrix contains about 10 to 50 vol % of a material capable of absorbing a liquid solvent, typically water, to provide a plurality of ion conducting pathways through the matrix. The matrix also contains about 5 to 40 vol % of a chemical species which is able to undergo either oxidation or reduction during operation of the device. Preferably, the solvent absorbing material is a hydrophilic polymer such as polyvinylpyrrolidone. For the anodic electrode, the chemical species should be able to undergo oxidation and is preferably either silver or zinc. For the cathodic electrode, the chemical species should be able to undergo reduction and is preferably silver chloride or a reducible metal.

TECHNICAL FIELD

This invention relates to a device for delivering an agent transdermallyor transmucosally by iontophoresis. More particularly, this inventionrelates to an electrically powered iontophoretic delivery device havinga polymer-based electrode.

BACKGROUND ART

Iontophoresis, according to Dorland's Illustrated Medical Dictionary, isdefined to be "the introduction, by means of electric current, of ionsof soluble salts into the tissues of the body for therapeutic purposes."Iontophoretic devices have been known since the early 1900's. Britishpatent specification No. 410,009 (1934) describes an iontophoreticdevice which overcame one of the disadvantages of such early devicesknown to the art at that time, namely the requirement of a special lowtension (low voltage) source of current which meant that the patientneeded to be immobilized near such source. The device of that Britishspecification was made by forming a galvanic cell from the electrodesand the material containing the medicament or drug to be deliveredtransdermally. The galvanic cell produced the current necessary foriontophoretically delivering the medicament. This ambulatory device thuspermitted iontophoretic drug-delivery with substantially lessinterference with the patient's daily activities.

More recently, a number of United States patents have issued in theiontophoresis field, indicating a renewed interest in this mode of drugdelivery. For example, U.S. Pat. No. 3,991,755 issued to Vernon et al;U.S. Pat. No. 4,141,359 issued to JaCobsen et al; U.S. Pat. No.4,398,545 issued to Wilson; and as U.S. Pat. No. 4,250,878 issued toJacobsen disclose examples of iontophoretic devices and someapplications thereof. The iontophoresis process has been found to beuseful in the transdermal administration of medicaments or drugsincluding lidocaine hydrochloride, hydrocortisone, fluoride, penicillin,dexamethasone sodium phosphate, insulin and many other drugs. Perhapsthe most common use of iontophoresis is in diagnosing cystic fibrosis bydelivering pilocarpine salts iontophoretically. The pilocarpinestimulates sweat production; the sweat collected and analyzed for itschloride content to detect the presence of the disease.

In presently known iontophoretic devices, at least two electrodes areused. Both of these electrodes are disposed so as to be in intimateelectrical contact with some portion of the skin of the body. Oneelectrode, called the active or donor electrode, is the electrode fromwhich the ionic substance, medicament, drug precursor or drug isdelivered into the body by iontophoresis. The other electrode, calledthe counter or return electrode, serves to close the electrical circuitthrough the body. In conjunction with the patient's skin contacted bythe electrodes, the circuit is completed by connection of the electrodesto a source of electrical energy, e.g., a battery. For example, if theionic substance to be delivered into the body is positively charged(i.e., a cation), then the anode will be the active electrode and thecathode will serve to complete the circuit. If the ionic substance to bedelivered is negatively charged (i.e., an anion), then the cathode willbe the active electrode and the anode will be the counter electrode.

Alternatively, both the anode and cathode may be used to deliver drugsof opposite charge into the body. In such a case, both electrodes areconsidered to be active or donor electrodes. For example, the anode candeliver a positively charged ionic substance into the body while thecathode can deliver a negatively charged ionic substance into the body.

It is also known that iontophoretic delivery devices can be used todeliver an uncharged drug or agent into the body. This is accomplishedby a process called electroosmosis. Electroosmosis is the transdermalflux of a liquid solvent (e.g., the liquid solvent containing theuncharged drug or agent) which is induced by the presence of an electricfield imposed across the skin by the donor electrode. As used herein,the terms "iontophoresis" and "iontophoretic" refer to (1) the deliveryof charge drugs or agents by electromigration, (2) the delivery ofuncharged drugs or agents by the process of electroosmosis, (3) thedelivery of charged drugs or agents by the combined processes ofelectromigration and electroosmosis, and/or (4) the delivery of amixture of charged and uncharged drugs or agents by the combinedprocesses of electromigration and electroosmosis.

Furthermore, existing iontophoresis devices generally require areservoir or source of the beneficial agent (which is preferably anionized or ionizable agent or a precursor of such agent) to beiontophoretically delivered into the body. Examples of such reservoirsor sources of ionized or ionizable agents include a pouch as describedin the previously mentioned Jacobsen U.S. Pat. No. 4,250,878, or apre-formed gel body as described in Webster U.S. Pat. No. 4,383,529 andAriura et al. U.S. Pat. No. 4,474,570. Such drug reservoirs areelectrically connected to the anode or the cathode of an iontophoresisdevice to provide a fixed or renewable source of one or more desiredagents.

More recently, iontophoretic delivery devices have been developed inwhich the donor and counter electrode assemblies have a "multi-laminate"construction. In these devices, the donor and counter electrodeassemblies are each formed by multiple layers of (usually) polymericmatrices. For example, Parsi U.S. Pat. No. 4,731,049 discloses a donorelectrode assembly having hydrophilic polymer based electrolytereservoir and drug reservoir layers, a skin-contacting hydrogel layer,and optionally one or more semipermeable membrane layers. Sibalis U.S.Pat. No. 4,640,689 discloses in FIG. 6 an iontophoretic delivery devicehaving a donor electrode assembly comprised of a donor electrode (204),a first drug reservoir (202), a semipermeable membrane layer (200), asecond drug reservoir (206), and a microporous skin-contacting membrane(22'). The electrode can be formed of a carbonized plastic, metal foilor other conductive films such as a metallized mylar film. In addition,Ariura et al, U.S. Pat. No. 4,474,570 discloses a device wherein theelectrode assemblies include a conductive resin film electrode layer, ahydrophilic gel reservoir layer, a current distribution and conductinglayer and an insulating backing layer. Ariura et al disclose severaldifferent types of electrode layers including an aluminum foilelectrode, a carbon fiber non-woven fabric electrode and acarbon-containing rubber film electrode.

Others have suggested using biomedical electrodes having currentdistribution members composed of a rubber or other polymer matrix loadedwith a conductive filler such as powdered metal. See for example, U.S.Pat. No. 4,367,745. Such films however, have several disadvantages.First, as metal particle loading in a polymer matrix approaches about 65vol %, the-matrix begins to break down and becomes too brittle to behandled. Even at metal particle loadings of only about 50 to 60 vol %,the films produced are extremely rigid and do not conform well tonon-planar surfaces. This is a particular disadvantage when designing anelectrode adapted to be worn on the skin or a mucosal membrane. Aniontophoretic electrode adapted to be worn on a body surface must havesufficient flexibility to contour itself to the natural shape of thebody surface to which it is applied.

The drug and electrolyte reservoir layers of iontophoretic deliverydevices have been formed of hydrophilic polymers. See for example,Ariura et al, U.S. Pat. No. 4,474,570; Webster U.S. Pat. No. 4,383,529and Sasaki U.S. Pat. No. 4,764,164. There are several reasons for usinghydrophilic polymers. First, water is the preferred solvent for ionizingmany drug salts. Secondly, hydrophilic polymer components (i.e., thedrug reservoir in the donor electrode and the electrolyte reservoir inthe counter electrode) can be hydrated while attached to the body byabsorbing water from the skin (i.e., through transepidermal water lossor sweat) or from a mucosal membrane (e.g., by absorbing saliva in thecase of oral mucosal membranes). Once hydrated, the device begins todeliver ionized agent to the body. This enables the drug reservoir to bemanufactured in a dry state, giving the device a longer shelf life.

The prior art has also recognized that certain electrode compositionsare preferred from the standpoint of drug delivery efficiency andminimizing skin burns caused by pH extremes. For example, U.S. Pat. Nos.4,744,787; 4,747,819 and 4,752,285 all disclose iontophoretic electrodeswhich are either oxidized or reduced during operation of the device.Preferred electrode materials include a silver anodic electrode, whichis used to deliver the chloride salt of a drug, and a silver/silverchloride cathodic (return) electrode. Silver ions generated at the anodecombine with the drug counter ion (i.e., chloride ions) to produce aninsoluble silver chloride precipitate. This reduces competition betweenthe drug ions and the silver ions for delivery into the body andincreases the efficiency of the device.

DISCLOSURE OF THE INVENTION

It is an object of this invention to provide an improved electrode foran iontophoretic delivery device.

This and other objects are met by an electrically powered iontophoreticdelivery device including a donor electrode assembly, a counterelectrode assembly and a source of electrical power adapted to beelectrically connected to the donor and counter electrode assemblies. Atleast one of the donor and counter electrode assemblies includes anagent reservoir containing an agent, the agent reservoir adapted to beplaced in agent transmitting relation with a body surface, and anelectrode adapted to be electrically connected to the source ofelectrical power and to the agent reservoir. The electrode comprises apolymeric matrix containing about 5 to 40 vol % of a chemical specieswhich is able to undergo either oxidation or reduction during operationof the device and about 10 to 50 vol % of an agent capable of absorbinga liquid solvent (e.g., water) and thereby forming a plurality ofion-conducting pathways through the matrix.

When the electrode is an anode, the chemical species is able to undergooxidation and is preferably an oxidizable metal such as silver or zinc.When the electrode is a cathode, the chemical species is able to undergoreduction during operation of the device, and is preferably silverchloride or a reducible metal. The solvent-absorbing agent is preferablyformed of a hydrophilic polymer which is substantially insoluble in thesolvent.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic view of an iontophoretic drug delivery deviceaccording to the present invention; and

FIG. 2 is a schematic view of another embodiment of an iontophoreticdelivery device according to the present invention.

MODES FOR CARRYING OUT THE INVENTION

FIG. 1 is a schematic view of an iontophoretic delivery device 10 fordelivering a beneficial agent through a body surface 22. Body surface 22is typically intact skin or a mucosal membrane. Iontophoretic deliverydevice 10 includes a donor electrode assembly 8, a counter electrodeassembly 9, an electrical power source 27 (e.g., a battery) and anoptional control circuit 19.

The donor electrode assembly 8 includes a donor electrode 11 and anagent reservoir 15. The agent reservoir 15 contains the beneficial agentto be iontophoretically delivered by device 10. The donor electrodeassembly 8 is adhered to the body surface 22 by means of anion-conducting adhesive layer 17.

Iontophoretic delivery device 10 includes a counter electrode assembly 9which is placed on the body surface 22 at a location spaced apart fromelectrode assembly 8. Counter electrode assembly 9 includes a counterelectrode 12 and an electrolyte reservoir 16. Counter electrode assembly9 is adhered to the body surface 22 by means of an ion-conductingadhesive layer 18. The donor and counter electrode assemblies 8 and 9normally include a strippable release liner, not shown, which is removedprior to application of electrode assemblies 8 and 9 to body surface 22.

The electrolyte reservoir 16 contains a pharmacologically acceptablesalt. Suitable electrolytes for reservoir 16 include sodium chloride,alkaline salts, chlorides, sulfates, nitrates, carbonates, phosphates,and organic salts such as ascorbates, citrates, acetates and mixturesthereof. Reservoir 16 may also contain a buffering agent. Sodiumchloride is a suitable electrolyte when the counter electrode 12 is thecathode and is composed of silver/silver chloride, optionally with asodium phosphate buffer.

When the device 10 is in storage, no current flows because the deviceforms an open circuit. When the device 10 is placed on the skin ormucosal membrane of a patient and reservoirs 15 and 16, layers 17 and18, and electrodes 11 and 12 become sufficiently hydrated to allowconduction of ions therethrough, the circuit between the electrodes isclosed and the power source begins to deliver current through the deviceand through the body of the patient. Electrical current flowing throughthe conductive portions of the device 10 (i.e., those portions used toconnect the power source 27 to the electrodes 11 and 12) is carried byelectrons (electronic conduction), while current flowing through thehydrated portions of the device 10 (e.g., the electrodes 11 and 12, theagent reservoir 15, the electrolyte reservoir 16 and the ion-conductingadhesive layers 17 and 18) is carried by ions (ionic conduction). Inorder for current to flow through the device, it is necessary forelectrical charge to be transferred from power source 27 to chemicalspecies in solution in electrodes 11 and 12, respectively, by means ofoxidation and reduction charge transfer reactions within the electrodes11 and 12.

Electrodes 11 and 12 are each comprised of a hydrophobic polymericmatrix. The matrix contains about 10 to 50 vol % of an agent which iscapable of absorbing a liquid solvent, typically an aqueous solvent, andthereby forming ion-conducting pathways through the matrix. The matrixalso contains about 5 to 40 vol % of a chemical species which is able toundergo either oxidation or reduction during operation of the device.The polymer used as the matrix for electrodes 11 and 12 is preferablyselected from hydrophobic polymers which can be suitably mixed with thesolvents absorbing agent and the chemical species able to undergooxidation or reduction. As used herein, a hydrophobic polymer is anypolymer having an equilibrium water content of less than 20 wt %,preferably less than about 15 wt % and most preferably less than about10 wt % after prolonged exposure to an atmosphere having a relativehumidity of over about 90%. Examples of suitable polymers for use as thematrix of electrodes 11 and 12 include, without limitation, polyalkenes,polyisoprenes, rubbers such as polyisobutylene, ethylene vinyl acetatecopolymers, polyamides, polyurethanes, polyvinylchloride, modifiedcellulosic polymers, highly cross-linked polyethylene oxides andmixtures thereof. Preferred hydrophobic polymeric matrices forelectrodes 11 and 12 include polyisobutylenes, copolymers of ethylenevinyl acetate and mixtures thereof.

The polymeric matrix of electrodes 11 and 12 contains about 5 to 40 vol%, preferably about 15 to 30 vol %, and most preferably about 20 to 25vol % of a chemical species which is able to undergo either oxidation orreduction during operation of the device. As mentioned above, aselectrical current flows through device 10, oxidation or reduction ofsome chemical species takes place within at least one of the electrodes11 and 12. Most typically, oxidation of an oxidizable chemical speciestakes place within the anode while reduction of a reducible chemicalspecies takes place within the cathode. Although a variety ofelectrochemical reactions can be utilized, the present inventionutilizes a class of charge transfer reactions whereby a portion of atleast one of the electrodes 11 and 12 participates in a chargetransferring chemical reaction, i.e., a material in at least one of theelectrodes 11 and 12 is consumed or generated. This is accomplishedthrough oxidation and/or reduction reactions Occurring within theelectrodes. Examples of preferred oxidation/reduction reactions includethe following:

    Ag=Ag.sup.+ +e.sup.-

    Zn=Zn.sup.+2 +2e.sup.-

    Cu=Cu.sup.+2 +2e.sup.-

    Ag+Cl.sup.- =AgCl+e.sup.-

    Zn+2Cl.sup.- =ZnCl.sub.2 +2e.sup.-

where the forward reaction is the oxidation reaction taking place in theanodic electrode and the reverse reaction is the reduction reactiontaking place in the cathodic electrode. Other standard electrochemicalreactions and their respective reduction potentials are well known inthe art. See the CRC Handbook of Chemistry and Physics, pp D 151-58,67th edition (1986-1987).

If the electrode is to be used as an anode, the chemical species shouldbe able to undergo oxidation during operation of the device. Suitablechemical species able to undergo oxidation include electricallyconductive metals such as silver, zinc, copper, nickel, tin, lead, ironand chromium. Other oxidizable species are listed in the CRC Handbook ofChemistry and Physics, 57th edition, D-141 to D-146. Preferred chemicalspecies able to undergo oxidation are electrically conductive metals,preferably in the form of powders. Most preferred are silver and zincpowders. Although non-conductive oxidizable chemical species can also beused, they require an additional electrically conductive filler in thepolymeric matrix. Suitable conductive fillers include carbon or graphitefibers, carbon or graphite powders and powdered metals.

If the electrode is to be used as a cathode, the chemical species shouldbe able to undergo reduction during operation of the device. Suitablechemical species which are able to undergo reduction include silverchloride, silver bromide, silver hexacyanoferrate, cupric sulfate,cupric chloride and other reducible species listed in the CRC Handbookof Chemistry and Physics, 57th edition, D-141 to D-146. Preferably, thereducible chemical species is also electrically conductive. Of these, ssilver chloride is most preferred. Although non-conductive reduciblechemical species (e.g., cupric sulfate and cupric chloride) can also beused, they require an additional electrically conductive filler in thepolymeric matrix. Suitable conductive fillers include carbon or graphitefibers, carbon or graphite powders and powdered metals.

Electrodes 11 and 12, once hydrated, each have a plurality of liquidsolvent-containing pathways running therethrough. These pathways can beformed by mixing a sufficient quantity, generally about 10 to 50 vol %,preferably about 20 to 35 vol % and most preferably about 25 to 30 vol%, of an agent capable of absorbing a solvent, such as water, throughoutthe matrices of electrodes 11 and 12. Electrodes 11 and 12 can bemanufactured in a non-hydrated condition, thereby giving the electrodesand the device a longer and more stable shelf life. Water, and/oranother liquid solvent, can then be applied to the electrodes at thetime of use. The solvent absorbing agent absorbs the liquid solvent(e.g., water) thereby forming ion-conducting pathways through thematrices of electrodes 11 and 12. In certain situations wherein theagent reservoir 15 and the electrolyte reservoir 16 are alsomanufactured in a dry (e.g., non-hydrated) state, these same pathwayscan be used to conduct liquid solvent into the non-hydrated drug and/orelectrolyte reservoirs and/or ion-conducting adhesive layers in order tohydrate these additional layers and place the device in an operational(e.g., hydrated) condition.

The agent which is capable of absorbing a liquid solvent and therebyforming ion-conducting pathways through electrodes 11 and 12 aretypically water absorbent materials since the preferred medium forconducting transdermal iontophoretic drug delivery is aqueous based.Preferred solvent-absorbing agents are hydrophilic polymers which aresubstantially water insoluble. As used herein, a hydrophilic polymer isa polymer having an equilibrium water content of at least 20 wt %,preferably at least about 30 wt % and most preferably at least about 40wt % after prolonged exposure to an atmosphere having a relativehumidity of over about 90%. Examples of suitable hydrophilic waterinsoluble polymers include polyvinylpyrrolidones, hydrogels such aspolyethylene oxides, Polyox®, Polyox® blended with polyacrylic acid orCarbopol®, Carbowaxes®, highly crystallized polyvinyl alcohols,cellulose derivatives such as hydroxypropyl methyl cellulose,hydroxypropyl cellulose, mixtures of highly crystallized polyvinylalcohols and hydroxypropyl methyl cellulose, insoluble starchderivatives, such as starch-graft poly(Na acrylate co-acrylamide)polymers sold under the tradename Waterlock® by Grain Processing Corp.,Muscatine, IA, and the like, along with blends thereof.

FIG. 2 illustrates another iontophoretic delivery device designated bythe numeral 20. Like device 10, device 20 also contains an electricalpower source 27 (e.g., a battery) and an optional control circuit 19.However, in device 20 the donor electrode assembly 8 and the counterelectrode assembly 9 are physically attached to an insulator 26 and forma single self-contained unit. Insulator 26 prevents the electrodeassemblies 8 and 9 from short circuiting by preventing electrical and/orion transport between the electrode assemblies 8 and 9. Insulator 26 ispreferably formed of a hydrophobic non-conducting polymeric materialwhich is impermeable to both the passage of ions and water. A preferredinsulating material is a nonporous ethylene vinyl acetate copolymer.

Alternatively, both the donor electrode assembly 8 and the counterelectrode assembly 9 may be used to iontophoretically deliver differentbeneficial agents through body surface 22. For example, positive agentions can be delivered through body surface 22 from the anodic electrodeassembly, while negative agent ions can be delivered from the cathodicelectrode assembly. Alternatively, neutral drugs can be introduced fromeither electrode assembly by electroosmosis.

As an alternative to the side-by-side alignment of the donor electrodeassembly 8, the insulator 26 and the counter electrode assembly 9 shownin FIG. 2, the electrode assemblies can be concentrically aligned withthe counter electrode assembly positioned centrally and surrounded bythe insulator 26 and the donor electrode assembly. The electrodeassemblies can, if desired, be reversed with the counter electrodeassembly surrounding the centrally positioned donor electrode assembly.The concentric alignment of the electrode assemblies can be circular,elliptical, rectangular or any of a variety of geometric configurations.

Power source 27 is typically one or more batteries. As an alternative toa battery, device 10 can be powered by a galvanic couple formed by thedonor electrode 11 and counter electrode 12 being composed of dissimilarelectrochemical couples and being placed in electrical contact with oneother. Typical materials for delivering a cationic agent into the bodyinclude a zinc donor electrode 11 and a silver/silver chloride counterelectrode 12. A Zn-Ag/AgCl galvanic couple provides an electricalpotential of about 1 volt.

The agent and electrolyte reservoirs 15 and 16 can be formed by blendingthe desired agent, drug, electrolyte or other component(s), with thepolymer by melt blending, solvent casting or extrusion, for example. Thedrug and/or electrolyte loading in the polymer matrix is generally about10 to 60 wt %, although drug and/or electrolyte loadings outside thisrange may also be used.

Suitable polymers for use as the matrix of reservoirs 15 and 16 include,without limitation, hydrophobic polymers such as polyethylene,polypropylene, polyisoprenes and polyalkenes, rubbers such aspolyisobutylene, copolymers such as Kraton®, polyvinylacetate, ethylenevinyl acetate copolymers, polyamides including nylons, polyurethanes,polyvinylchloride, cellulose acetate, cellulose acetate butyrate,ethylcellulose, cellulose acetate, and blends thereof; and hydrophilicpolymers such as hydrogels, polyvinylpyrrolidones, polyethylene oxides,Polyox®, Polyox® blended with polyacrylic acid or Carbopol®, cellulosederivatives such as hydroxypropyl methyl cellulose, hydroxyethylcellulose, hydroxypropyl cellulose, pectin, starch, guar gum, locustbean gum, and the like, along with blends thereof.

The adhesive properties of the reservoirs 15 and 16 may be enhanced byadding a resinous tackifier. This is especially important when using anon-tacky polymeric matrix. Examples of suitable tackifiers includeproducts sold under the trademarks Staybelite Ester #5 and #10,Regal-Rez and Piccotac, all sold by Hercules, Inc. of Wilmington, Del.Additionally, the matrix may contain a rheological agent, suitableexamples of which include mineral oil and silica.

In addition to the drug and electrolyte, the reservoirs 15 and 16 mayalso contain other conventional materials such as buffers, dyes,pigments, inert fillers, and other excipients.

A control circuit 19 is optionally provided. Control is circuit 19 maytake the form of an on-off switch for "on-demand" drug delivery (e.g.,on-demand delivery of an analgesic for pain control), a timer, a fixedor variable electrical resistor, a controller which automatically turnsthe device on and off at some desired periodicity to match the naturalor circadian patterns of the body, or other more sophisticatedelectronic control devices known in the art. For example, it may bedesirable to deliver a predetermined constant level of currentfrom-device 10 since a constant current level ensures that the drug oragent is delivered through the skin at a constant rate. The currentlevel can be controlled by a variety of known means, for example, aresistor or a field effect transistor or a current limiting diode.Control circuit 19 may also include a microchip which could beprogrammed to control the dosage of beneficial agent, or even to respondto sensor signals in order to regulate the dosage to maintain apredetermined dosage regimen. A relatively simple controller ormicroprocessor can control the current as a function of time, and ifdesired, generate complex current waveforms such as pulses or sinusoidalwaves. In addition, the control circuit 19 may employ a bio-feedbacksystem which monitors a biosignal, provides an assessment of thetherapy, and adjusts the drug delivery accordingly. A typical example isthe monitoring of the blood sugar level for controlled administration ofinsulin to a diabetic patient.

As used herein, the expression "agent" can mean a drug or otherbeneficial therapeutic agent when referring to the donor electrodeassembly and/or an electrolyte salt when referring to the counterelectrode assembly. The expressions "drug" and "therapeutic agent" areused interchangeably and are intended to have their broadestinterpretation as any therapeutically active substance which isdelivered to a living organism to produce a desired, usually beneficial,effect. In general, this includes therapeutic agents in all of the majortherapeutic areas including, but not limited to, anti-infectives such asantibiotics and antiviral agents, analgesics and analgesic combinations,anesthetics, anorexics, antiarthritics, antiasthmatic agents,anticonvulsants, antidepressants, antidiabetic agents, antidiarrheals,antihistamines, anti-inflammatory agents, antimigraine preparations,antimotion sickness preparations, antinauseants, antineoplastics,antiparkinsonism drugs, antipruritics, antipsychotics, antipyretics,antispasmodics, including gastrointestinal and urinary,anticholinergics, sympathomimetrics, xanthine derivatives,cardiovascular preparations including calcium channel blockers,beta-blockers, antiarrythmics, antihypertensives, diuretics,vasodilators, including general, coronary, peripheral and cerebral,central nervous system stimulants, cough and cold preparations,decongestants, diagnostics, hormones, hypnotics, immunosuppressives,muscle relaxants, parasympatholytics, so parasympathomimetrics,proteins, peptides, psychostimulants, sedatives and tranquilizers.

The invention is also useful in the controlled delivery or peptides,polypeptides, proteins and other macromolecules. These macromolecularsubstances typically have a molecular weight of at least about 300daltons, and more typically a molecular weight in the range of about 300to 40,000 daltons. Specific examples of peptides and proteins in thissize range include, without limitation, LHRH, LHRH analogs such asbuserelin, gonadorelin, naphrelin and leuprolide, GHRH, insulin,heparin, calcitonin, endorphin, TRH, NT-36 (chemical name:N=[[(s)-4-oxo-2-azetidinyl]carbonyl]-L-histidyl-L-prolinamide),liprecin, pituitary hormones (e.g., HGH, HMG, HCG, desmopressin acetate,etc.), follicle luteoids, αANF, growth factor releasing factor (GFRF),βMSH, somatostatin, bradykinin, somatotropin, platelet-derived growthfactor, asparaginase, bleomycin sulfate, chymopapain, cholecystokinin,chorionic gonadotropin, corticotropin (ACTH), erythropoietin,epoprostenol (platelet aggregation inhibitor), glucagon, hyaluronidase,interferon, interleukin-2, menotropins (urofollitropin (FSH) and LH),oxytocin, streptokinase, tissue plasminogen activator, urokinase,vasopressin, ACTH analogs, ANP, ANP clearance inhibitors, angiotensin IIantagonists, antidiuretic hormone agonists, antidiuretic hormoneantagonists, bradykinin antagonists, CD4, ceredase, CSF's, enkephalins,FAB fragments, IgE peptide suppressors, IGF-1, neurotrophic factors,parathyroid hormone and agonists, parathyroid hormone antagonists,prostaglandin antagonists, pentigetide, protein C, protein S, renininhibitors, thymosin alpha-1, thrombolytics, TNF, vaccines, vasopressinantagonist analogs, alpha-1 anti-trypsin (recombinant). It is mostpreferable to use a water soluble salt of the drug or agent to bedelivered.

The combined skin-contacting areas of electrode assemblies 8 and 9 canvary from less than 1 cm² to greater than 200 cm². The average device 10however, will have electrode assemblies with a combined skin-contactingarea within the range of about 5 to 50 cm².

As an alternative to the ion-conducting adhesive layers 17 and 18 shownin FIGS. 1 and 2, the iontophoretic delivery devices 10 and 20 may beadhered to the skin using an adhesive overlay. Any of the conventionaladhesive overlays used to secure passive transdermal delivery devices tothe skin may be used. Another alternative to the ion-conducting adhesivelayers 17 and 18 is a peripheral adhesive layer surrounding reservoir 15and/or 16, allowing reservoir 15 and/or 16 to have a surface in directcontact with the patient's skin.

Having thus generally described our invention, the following exampleswill illustrate preferred embodiments thereof.

EXAMPLE I

An anodic electrode was made by mixing powdered silver and cross-linkedpolyvinylpyrrolidone into a polyisobutylene matrix. First, 11.4 g ofpolyisobutylene (PIB) having a molecular weight of 1,200,000 (sold byExxon Corp. of Irving, Tex.) were added to a 50 cm³ Brabender mixer(Brabender Instruments, Inc., South Hackensack, N.J.). The mixer bowlwas preheated to 80° C. and the blade speed was set at 30 rpm. Then,11.4 g of PIB having a molecular weight of 35,000 (sold by Exxon Corp.of Irving, Tex.) was slowly added to the mixer. The PIB's were mixed forabout five minutes until they were well mixed. Thereafter, 11.3 g ofpolyvinylpyrrolidone, sold by GAF Corp. of Wayne, N.J. and having adegree of cross-linking of 10%, were slowly added into the mixer over aperiod of about five minutes. Thereafter, 118.1 g of silver powderhaving an average particle size of about 8 microns were slowly added tothe mixer over a period of about 15 minutes. Mixing was continued for anadditional 30 minutes.

Five batches of the material (about 250 cm³) were then loaded into aBrabender extruder having a 0.75 inch screw. The temperature at thescrew was about 110° C. An adjustable sheet extrusion die having a dieopening with a width of 4 inches and a height adjustable between 1 and40 mils was mounted at the end of the extruder. The temperature of thefilm at the die opening was 110° C. After extrusion, the film was passedbetween opposing calender rolls heated to about 105° C. The calenderedfilm had a thickness of 6 mils.

The film exhibited a voltage drop of less than 0.5 volts when a currentdensity of 100 μA/cm² of direct current was passed through the film.

Experiments were conducted to evaluate the electrochemical performanceof the anodic film electrode in comparison with the electrochemicalperformance of an electrode composed of pure silver. The apparatus usedto measure the electrochemical performance of the electrodes included acell containing an electrolyte solution and means for connecting ananode and a cathode within the cell. The electrodes of the cell areconnected in series with a potentiostat which is set to supply thenecessary voltage to maintain a constant current level of 100 μA/cm²through the circuit. Normal saline was used as the liquid electrolytesolution in the cell. The cell voltage required to pass 100 μA/cm² ofcurrent was monitored as a function of time for a period of 24 hours.

A control experiment used pure silver as the anode, a silver chloridecathode and the saline electrolyte. The cell voltage was monitored andrecorded over a 24 hour test period. A duplicate experiment was run withthe Ag/PVP/PIB anodic film electrode. The cathodic electrode in both thecontrol and actual experiments was composed of AgCl. Over the entire 24hour test period, the measured cell voltage of the anodic film electrodewas less than 0.3 volts greater than the measured cell voltage of thepure silver electrode. This small increase in the measured cell voltageis considered to be acceptable for an electrode used in a transdermaliontophoretic delivery device. In general, electrode materials requiringthe least amount of additional voltage to deliver the required amount ofelectrical current are most preferred. Accordingly, the anodic filmelectrode of the present invention exhibits an electrochemicalperformance that is only marginally below the-performance of a puresilver anodic electrode.

EXAMPLE II

A cathodic electrode was made by mixing silver chloride powder andcross-linked polyvinylpyrrolidone into a polyisobutylene matrix. First,11.4 g of polyisobutylene (PIB) having a molecular weight of 1,200,000were added to a 50 cm³ Brabender mixer. The mixer bowl was preheated to80° C. and the blade speed was set at 30 rpm. Thereafter, 11.4 g of PIBhaving a molecular weight of 35,000 was slowly added to the mixer. ThePIB's were mixed for about five minutes until they were well mixed.Thereafter, 11.3 g of cross-linked polyvinylpyrrolidone (PVP) wereslowly added into the mixer over a period of about five minutes.Thereafter, 62.6 g of granular silver chloride having a particle size ofless than 100 microns were .slowly added to the mixer over a period ofabout five minutes. Thereafter, the blade speed was maintained at 30 rpmfor an additional 30 minutes of mixing.

Five batches of the material (about 250 cm³) were then loaded into thesame extruder/die combination described in Example I. The temperature atthe screw was about 105° C. The temperature of the film at the dieopening was about 130° C. After extrusion, the film was passed betweenopposing calender rolls heated to about 160° C. The calendered film hada thickness of 6 mils.

The cathodic film exhibited a voltage drop of less than 0.5 volts when acurrent density of 100 μA/cm² of direct current was passed through thefilm.

Experiments were conducted to evaluate the electrochemical performanceof the AgCl/PVP/PIB cathodic film electrode in comparison with theelectrochemical performance of an electrode composed of sintered silverchloride, using the same apparatus and procedures described in ExampleI. The anodic electrode in both the control and actual experiments wascomposed of pure silver. Over the entire 24 hour test period, themeasured cell voltage of the cathodic film electrode was less than 0.3volts greater than the measured cell voltage of the sintered silverchloride electrode. This small increase in the measured cell voltage isconsidered to be acceptable for an electrode used in a transdermaliontophoretic delivery device. In general, electrode materials requiringthe least amount of additional voltage to deliver the required amount ofelectrical current are most preferred. Accordingly, the cathodic filmelectrode of the present invention exhibits an electrochemicalperformance that is only marginally below the performance of a sinteredsilver chloride cathodic electrode.

Having thus generally described our invention and described in detailcertain preferred embodiments thereof, it will be readily apparent thatvarious modifications to the invention may be made by workers skilled inthe art without departing from the scope of this invention and which islimited only by the following claims.

What is claimed is:
 1. An electrically powered iontophoretic deliverydevice including a donor electrode assembly, a counter electrodeassembly and a source of electrical power adapted to be electricallyconnected to the donor electrode assembly and the counter electrodeassembly, at least one of the electrode assemblies including an agentreservoir containing an agent, the agent reservoir adapted to be placedin agent transmitting relation with a body surface; and an electrodeadapted to be electrically connected to the source of electrical powerand to the agent reservoir; wherein the electrode comprises:ahydrophobic polymeric matrix; about 10 to 50 vol % of an agent which canabsorb a liquid solvent thereby forming a plurality of ion-conductingpathways through the matrix; and about 5 to 40 vol % of a chemicalspecies able to undergo oxidation or reduction during operation of thedevice.
 2. The device of claim 1, wherein the electrode is an anode andthe chemical species is an electrically conductive metal able to undergooxidation during operation of the device.
 3. The device of claim 2,wherein the metal is selected from the group consisting of silver andzinc.
 4. The device of claim 1, wherein the electrode is a cathode andthe chemical species is able to undergo reduction during operation ofthe device.
 5. The device of claim 4, wherein the chemical species ableto undergo reduction is an electrically conductive salt selected fromthe group consisting of AgCl, AgBr, and Ag₄ Fe(CN)₆.
 6. The device ofclaim 4, wherein the chemical species able to undergo reduction iselectrically non-conductive and the matrix also contains an electricallyconductive filler.
 7. The device of claim 6, wherein the electricallynonconductive reducible species is selected from the group consisting ofCuCl₂ and CuSO₄ and the conductive filler is comprised of a metal orcarbon.
 8. The device of claim 1, wherein the solvent-absorbing agent issubstantially insoluble in the solvent.
 9. The device of claim 1,wherein the solvent absorbing agent comprises a water-insolublehydrophilic polymer.
 10. The device of claim 9, wherein the hydrophilicpolymer is selected from the group consisting of polyvinylpyrrolidones,polyethylene oxides, polyvinyl alcohols, cellulose derivatives,insoluble starch derivatives, hydrogels and mixtures thereof.
 11. Thedevice of claim 1, wherein the hydrophobic polymeric matrix is selectedfrom the group consisting of ethylene vinyl acetate copolymers,polyalkylenes, polyisoprenes, rubbers including polyisobutylenes,polyamides, polyurethanes, polyvinylchlorides, modified cellulosicpolymers and mixtures thereof.
 12. The device of claim 1, wherein thehydrophobic polymer matrix is in the form of a film.
 13. The device ofclaim 1, wherein the counter electrode assembly includes a counterelectrode adapted to be electrically connected to the source ofelectrical power and an electrolyte reservoir adapted to be placed inelectrolyte transmitting relation with the body surface, the counterelectrode being in electrical contact with the electrolyte reservoir;wherein the counter electrode comprises:a hydrophobic polymeric matrix;about 10 to 50 vol % of an agent which can absorb a liquid solventthereby forming a plurality of ion-conducting pathways through thematrix; and about 5 to 40 vol % of a chemical species able to undergooxidation or reduction during operation of the device.
 14. The device ofclaim 13, wherein the electrolyte reservoir is a polymeric matrixcomprised of about 10 to 60 wt % of a hydrophilic polymer about 10 to 60wt % of a hydrophobic polymer and up to about 50 wt % of theelectrolyte.
 15. The device of claim 1, wherein the donor electrodeassembly includes a donor electrode adapted to be electrically connectedto the source of electrical power and a drug reservoir adapted to beplaced in drug transmitting relation with the body surface, the donorelectrode having a surface which is in contact with the drug reservoir.16. The device of claim 15, wherein the drug reservoir is a polymericmatrix comprised of about 10 to 60 wt % of a hydrophilic polymer, about10 to 60 wt % of a hydrophobic polymer and up to about 50 wt % of thedrug.
 17. The device of claim 1, wherein the power source comprises abattery.
 18. The device of claim 1, wherein the agent comprises a drug.19. The device of claim 18, wherein the drug is a water soluble drugsalt.
 20. The device of claim 1, wherein the agent comprises anelectrolyte.
 21. The device of claim 20, wherein the electrolytecomprises a water soluble electrolyte salt.
 22. The device of claim 1,wherein the liquid solvent absorbing agent and the chemical species ableto undergo oxidation or reduction are one and the same material.
 23. Thedevice of claim 22, wherein said material comprises silver chloride. 24.The device of claim 22, wherein said material comprises silver/silverchloride.